CRRL269: a novel designer and renal-enhancing pGC-A peptide activator

Yang Chen, Gail J. Harty, Brenda K. Huntley, Seethalakshmi R. Iyer, Denise M. Heublein, Gerald E. Harders, Laura Meems, Shuchong Pan, S Jeson Sangaralingham, Tomoko Ichiki, John C Jr. Burnett

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The natriuretic peptides (NPs) B-type NP (BNP) and urodilatin (URO) exert renal protective properties via the particulate guanylyl cyclase A receptor (pGC-A). As a potential renal-enhancing strategy, we engineered a novel designer peptide that we call CRRL269. CRRL269 was investigated in human cell lines and in normal canines to define potential cardiorenal enhancing actions. The mechanism of its cardiorenal selective properties was also investigated. In vitro NP receptor activity was quantified with guanosine 3',5'-cyclic monophosphate generation. In vivo effects were determined in normal canine acute infusion studies. We observed that CRRL269 demonstrated enhanced pGC-A activity in renal compared with nonrenal cell lines. CRRL269 exerted enhanced resistance to neprilysin compared with URO. Importantly, CRRL269 exhibited significant and greater increases in urinary sodium excretion and diuresis, with less blood pressure reduction, than BNP or URO in normal canines. CRRL269 retained potent renin-angiotensin-aldosterone system (RAAS) suppressing properties shared by URO and BNP. Also, CRRL269 exerted less arterial relaxation and higher cAMP cardiomyocytes generation than BNP. CRRL269 possessed superior renal and pGC-A activating properties compared with BNP or URO in vitro. CRRL269 exerted enhanced renal actions while suppressing RAAS in vivo and with less hypotension compared with URO or BNP. Together, our study suggests that CRRL269 is a promising innovative renal-enhancing drug, with favorable protective actions targeting cardiorenal disease states through the pGC-A receptor.

Original languageEnglish (US)
Pages (from-to)R407-R414
JournalAmerican journal of physiology. Regulatory, integrative and comparative physiology
Volume314
Issue number3
DOIs
StatePublished - Mar 1 2018

Fingerprint

Kidney
Peptides
Canidae
Natriuretic Peptides
Renin-Angiotensin System
Cell Line
Neprilysin
Peptide Receptors
Brain Natriuretic Peptide
Diuresis
Cyclic GMP
Cardiac Myocytes
Hypotension
atrial natriuretic factor receptor A
Ularitide
Sodium
Blood Pressure
Pharmaceutical Preparations
In Vitro Techniques

Keywords

  • cGMP
  • natriuretic peptide
  • NEP
  • pGC-A
  • renal selective

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

CRRL269 : a novel designer and renal-enhancing pGC-A peptide activator. / Chen, Yang; Harty, Gail J.; Huntley, Brenda K.; Iyer, Seethalakshmi R.; Heublein, Denise M.; Harders, Gerald E.; Meems, Laura; Pan, Shuchong; Sangaralingham, S Jeson; Ichiki, Tomoko; Burnett, John C Jr.

In: American journal of physiology. Regulatory, integrative and comparative physiology, Vol. 314, No. 3, 01.03.2018, p. R407-R414.

Research output: Contribution to journalArticle

Chen, Yang ; Harty, Gail J. ; Huntley, Brenda K. ; Iyer, Seethalakshmi R. ; Heublein, Denise M. ; Harders, Gerald E. ; Meems, Laura ; Pan, Shuchong ; Sangaralingham, S Jeson ; Ichiki, Tomoko ; Burnett, John C Jr. / CRRL269 : a novel designer and renal-enhancing pGC-A peptide activator. In: American journal of physiology. Regulatory, integrative and comparative physiology. 2018 ; Vol. 314, No. 3. pp. R407-R414.
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AU - Heublein, Denise M.

AU - Harders, Gerald E.

AU - Meems, Laura

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AU - Ichiki, Tomoko

AU - Burnett, John C Jr.

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AB - The natriuretic peptides (NPs) B-type NP (BNP) and urodilatin (URO) exert renal protective properties via the particulate guanylyl cyclase A receptor (pGC-A). As a potential renal-enhancing strategy, we engineered a novel designer peptide that we call CRRL269. CRRL269 was investigated in human cell lines and in normal canines to define potential cardiorenal enhancing actions. The mechanism of its cardiorenal selective properties was also investigated. In vitro NP receptor activity was quantified with guanosine 3',5'-cyclic monophosphate generation. In vivo effects were determined in normal canine acute infusion studies. We observed that CRRL269 demonstrated enhanced pGC-A activity in renal compared with nonrenal cell lines. CRRL269 exerted enhanced resistance to neprilysin compared with URO. Importantly, CRRL269 exhibited significant and greater increases in urinary sodium excretion and diuresis, with less blood pressure reduction, than BNP or URO in normal canines. CRRL269 retained potent renin-angiotensin-aldosterone system (RAAS) suppressing properties shared by URO and BNP. Also, CRRL269 exerted less arterial relaxation and higher cAMP cardiomyocytes generation than BNP. CRRL269 possessed superior renal and pGC-A activating properties compared with BNP or URO in vitro. CRRL269 exerted enhanced renal actions while suppressing RAAS in vivo and with less hypotension compared with URO or BNP. Together, our study suggests that CRRL269 is a promising innovative renal-enhancing drug, with favorable protective actions targeting cardiorenal disease states through the pGC-A receptor.

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